Substituted 2-nitromethyl-4, 10-dioxo-5-hydroxy-1, 2, 3, 4, 4a, 9, 9a, 10-octahydroanthracenes



United States Patent SUBSTITUTED Z-NITROM'ETHYL 4,10 DIOXO-S- HYDROXY1,2,3,4,4a,9,9a,1ll OCTAHYDROAN- THRACENES Thomas Lynn Fields, PearlRiver, N.Y., Raymond George Wilkinson, Montvaic, N.J., and Andrew StevenKende, Hartsdale, N.Y., assignors to American Cyanamid Company,Stamford, Conn, a corporation of Maine No Drawing. Filed Get. 22, 1962,Ser. No. 232,398

6 Claims. (Cl. 269-471) This invention relates to new organic compoundsand, more particularly, is concerned with novel substituted 2-nitrornethyli,IO-dioxo-S-hydroxy 1,2,3,4,-4a,9,9a,10octahydroanthracenes and to methods ofpreparing these novel compounds.The novel substituted Z-nitromethyl- 4,.10-dioX-o-5-hydroxyl,2,3,4,4a,9,9a, octahydroanthracenes of the present invention may berepresented by the following general formula:

wherein X is hydrogen or halogen, R is hydrogen, carboxy, lowercarbalkoxy or phenyl lower carbalkoxy, and Z is hydrogen, lowercarbalkoxy or lower alkanoyl. Suitable lower car-balkoxy groupscontemplated by the present invention are those having up to about 6carbon atoms with carbomethoxy and carbethoxy being preferred. Suitablelower allcanoyl groups contemplated by the present invention are thosehaving up to about 6 carbon atoms with acetyl being referred. Suitablephenyl lower carballtoxy groups are, for example, carbobenzyioxy andcarbophenethoxy. Halogen is exemplified by chlorine and bromine. It isto be understood that the novel compounds of the present invention maytheoretically exist in other tautomeric forms.

The novel compounds of the present invention are particularly useful aschelating, ccmplexing or sequestering agents for polyvalent metallicions. The complexes formed with polyvalent metallic ions areparticularly stable and usually quite soluble in various organicsolvents. This, of course, makes them useful for a variety of purposessuch as in biological experimentation where the removal of traces ofpolyvalent metallic ions may be of great importance. They are alsouseful in analyses for polyvalent metallic ions which may be complexedand extracted by means of these reagents. Other uses common tosequestering agents are also apparent from these compounds.

The novel compounds of the present invention are obtainable ascrystalline materials having characteristic melting points andabsorption spectra. They are appreciably soluble in many organicsolvents such as lower alkanols, acetone, ethyl acetate, and the like.They are,

however, generally insoluble in Water. The novel compounds of thepresent invention are biologically active and have been found to possessantibacterial activity. The

minimal inhibitory concentrations, expressed in gammas per milliliter,of four typical compounds of the present invention againstStaphylococcus aureus when measured Patented June 29, 1955 by a standardturbidimetric procedure are set forth in the following table:

Furthermore, the3-oarbobenzyloxy-S-chloro-Z-nitrornethyl-4,10-dioxo-S-hydroxy-l,2,3,4,4a,9;9a,itoctahydroanthracene inhibits the growth of Mycobacterium ranae at aconcentration of 15 'y/ml. and inhibits the growth of Staphylococcusaureus 209P at a concentration of 62'y/ml.

The novel compounds of the present invention may also be useful in thesynthesis of physiologically active antibiotics of the tetracyclineseries. For example, when Z is hydrogen and R is lower carb-alokxy orphenyl lower carbalkoxy in the general formula set forth above, thesenovel compounds of the present invention may be converted by standardhydrolytic procedures to the intermediate Q-nitromethyl-B-carboxy 4,10dioxo 5 hydroxy- 1,2,3,4,4a,9,9a, 10-octahydroanthracenes. Theintermediates may then be converted to the corresponding acyl halides bytreatment with a suitable agent such as oxalyl chloride or thionylchloride, or alternatively, the mixed car-boXylic-carbonic vanhydridederivative may be prepared in the usual manner. The corresponding acylmalonate may then be prepared :by treating the intermediate acylderivative with sodium or magnesium diethylrnalonate.

. The acyl malonate may then be cyclized with a strongly basiccondensing agent such as sodium hydride, sodium metal, an alkali metalalkoxide, or the like, to the ethyl ester of the corresponding4-nitro-1,2,3,4,4-a,5,5a,6,11,1121, l2,1Za-dodecahydro-l,3, 1'1,l2tetraoxo 1O hydroxynaph-thacene-Z-carb'oxylic acids. Thesedodecahydronaphthacenes may then be reduced and methylated to give the4-dimethylamino derivative, which may in turn be treated to remove thecarbethoxy group by strong acid hydrolysis, or may be converted to the2-carboxamido derivative by treating with alcoholic ammonia at 0-110 C.in a sealed vessel.

The novel compounds of the present invention wherein R is hydrogen and Zis lower carbalkoxy or lower alkanoyl in the general formula set forthabove, may also be converted to physiologically active antibiotics ofthe tetracycline series in the following manner. The nitro group isfirst reduced to an amino group and methylated by standard reductivealkyl'ation procedures. This is followed by hydrolysis of the lowercarbalkoxy or lower allcanoyl group by standard hydrolytic procedures tothe intermediate 4, 1 O-dioxo-S -hydroXy-1 ,2,3,4,-4-a,9,9 a, lO-octahydro-Z-anthrylglycines. These intermediates may then be convertedto the corresponding acyl halides by treatment with a suitable agentsuch as oxalyl chloride or thionyl chloride, or alternatively, the mixedcarboxyliccarbonic anhydride derivative maybe prepared in the us ualmanner. The corresponding acyl mal-onate may then be prepared bytreating the intermediate acyl derivative 3 with sodium or magnesiumdiethylmalonate. The acyl malonate may then be cyclized with a stronglybasic condensing agent such as sodium hydride, sodium metal, an alkalimetal .alkoxide, or the like, to the ethyl ester of the corresponding4-dimethylamino 1,2,3,4,4a,'5,5a,6,-11,11a, 12,1221 dodecahydro 1,3,1l,12 tetraoxo 1O hydroxynaphth-acene-Z-carboxy'lic acids. Thesedodecahydron aphthacenes may then be treated to remove the carbethoxygroup by strong acid hydrolysis or may be converted to the 2-carboxamidoderivative by treating with alcoholic ammonia at 70 C.1 l C. in a sealedvessel.

The novel compounds of the present invention may be prepared by theMichael addition of a nitromethane derivative of the general formula:

wherein Z is as hereinabove defined, to a 1,4,4a,9,9a,l0-hexahydro-4,10-dioxo-S-hydroxyanthracene of the general formula:

wherein X and R are as hereinabove defined. The 1,4, 4'a,9,'9a,l0hexahydro 4,10 dioxo hydroxyanthracenes of the above general formulawhere R is carboxy, lower carballroxy or phenyl lower carbalkoxy aredisclosed and claimed in our copending application Serial No. 155,484,filed November 2 8, 1961. The 1, 4,4a,9,9a, \-hexahydro-4,10-dioxo 5hydroxyanthracenes may be readily prepared by a. series of reactionsstarting with the -5-hydroxy 1,2,3,4-tetrahydro '4 oxonaphthalene-Z-.acetaldehydes disclosed and claimed in the copending application ofRaymond G. Wilkinson et 211., Serial No. 821,093, filed June 18, 1959,now Patent No. 3,102,914. The 5-hydroxy1,2,3,-4-tetrahydro 4oxonaphthalene 2- acetaldehyde is first converted to the diethylS-hydroxy- 1,2,3,'4-tetrahydro 4 oxo 2 naphthylethylidene malon-ate bytreatment with diethyl malonate. This malonic ester is then subjected toa Diels-Alder condensation with cyclopentadiene whereby thecorresponding cycl-opentadiene adduct is obtained. Treatment of thecrude cyclopentadiene adduct with sodium hydride in refluxing toluenegives the desired 1,4,4a,9,9a,10-hexahydro-4,lO-dioxo-S-hydroxy-anthracene.

The Michael addition whereby the novel compounds of the presentinvention are prepared is preferably carried out in an anhydrous solventsuch as ethanol, benzene, toluene, diethyl ether, or the like, with astrongly basic condensing agent such as sodium hydride, sodium metal, analkali metal alkoxide, or the like. The reaction may be carried out overa wide range of temperatures limited,

in general, only by the properties of the solvent, over a period of timeof from as little as 10 minutes to about -12 hours or more.

The invention will be described in greater detail in conjunction withthe following specific examples.

A solution of diethyl 8-chloro-1,2,3,4-tetrahydro.- 5- hydroxy 4 0x0 2naphthylidene malonate (15.0 g.) and 8 ml. of freshly distilledcyclopentadiene in 10 ml. of toluene was placed in a bomb and heated to150 C. for 20 hours. Evaporation of the toluene in vacuo gave a brownoil. This crude Dials-Adler adduct was dissolved in 20 ml. of drytoluene, 10 g. of 50% sodium hydride dispersion was added, and thestirred suspension slowly brought to reflux under a nitrogen atmosphere.After three hours the ultraviolet absorption peak had shifted to adissyrnmetric peak with maximum at 349 Inn and considerable absorptionbetween 350 and 370 m The cooled reaction mixture was cautiouslyacidified by the gradual addition of glacial acetic acid followed by theaddition of 300 ml. of ethanol-ethyl acetate. The organic layer wasWashed with Water, dilute sodium bicarbonate solution and then driedover anhydrous magnesium sulfate. Evaporation of the solvent gave :2.yellow oil. Chromatography of this material on silica gel, using benzeneas the eluen-t, gave 1.12 g. of 8-chlorol,'4,4a, 9,9a;10-hexahydro-4;l0,diox-o 5 hydroxyanthracene, M.P. 150-15 1 C.; and also some ethyl1'O-chloro-1,4, 11,11a,-12,12a-hexahydro-5,7-dihydroxy-6-oxo 1,4methanonaphthacene 4a(6H) carboxylate.

Example 2.3 carbobenzyloucy 8 chloro 2 (1 -m'tr0- acetonyl) 4,10 dioxo 5hyclroxy 1,2,3,4,4a,9,9a, 10 octahydroanthracene To a stirred solutionof benzyl 8-chloro-5-hydroxy-1,4,4a,9,-9a,l0-hexahydro-4,=lO-dioxo-anthracene 3 carboxylate mg.) in drytoluene (8 ml.), under a nitrogen atmosphere, was added 50 mg. of a 50%sodium hydride in oil suspension followed immediately by 100 mg. ofnitroacetone. The mixture was stirred at room temperature for one hour.The reaction mixture was acidified by the cautious addition of glacialacetic acid. After dilution with 10 ml. of toluene the solution waswashed with 1 N hydrochloric acid and 4 times with water. The driedsolution was concentrated to an oily residue. Crystallization from ethergave a yellow crystalline, product; yield 42 mg; MP. 153-158 C.

Example 3.-3 carboxy 8 chloro 2 (1 nitroacetonyl) 4,10 dioxo 5 hydroxy1,2,3,4,4a,9,9a,10-0ctahydroan-tlzracene 3 carbobenzyloxy 8 chloro 2(1-nitroacetonyl)- 4,10-dioxo-5-hydroxy 1,2,-3;4,4a, 9,9a,'10octahydrc-anthracene (100 mg.) was dissolved in 20 ml. of methylCellosolve with the aid of heat. The solution was cooled in an ice bath,flushed with nitrogen and 20 mg. of 10% palladium on carbon was added.Hydrogen was then bubbled through the system at a vigorous rate and theefiluent gases were passed into a solution of barium hydroxide. After1.5 hours no barium carbon-ate precipitate was observed. The system wasflushed with nitrogen and the catalyst was removed by filtration. Thesolvent was removed by evaporation under vacuum, the temperature of thesolution being maintained at or below room temperature. Trituration ofthe residual yellow gum with ether yielded 31 mg. of analytically pure'3-carboxy-8- chloro 2 (1 nitroacetonyl) 4,10-dioxo-5-hydroxy-l,2,3,4,4a,9,9a,10 --cctahydroanthracene; MP. C. with the evolution ofgas.

Example 4.8 chloro 2 (1 nitroacetonyl)-4,10-

dioxo 5 hydroxy 1,2,3,4,4a,9,9a,10 0ctahydr0 anthracene 3 carbobenzyloxy8 chloro 2 ('1 nitroacetonyl)- 4,10 dioxo 5 hydroxy1,2,3,4,4-a,'9,9a,-10 octahydroanthracene (100 mg.) was dissolved in 1-5ml. of methyl C-ellosolve with warming. 15 mg. of 10% palladium oncarbon Was added and the mixture subjected to a hydrogen atmosphere fortwo hours. The catalyst was filtered off and the solvent was removed invac. with gentle warming. Recrystallization of the pale yellow solidfrom '5 ml. of ether gave 30 mg. of analytically pure S-chloro-Z- (1nitroacetonyl) 4,10 dioxo 5 hydroxy 1,2,3,4,4a,9,9a,l0-octanhydroanthracene; MP. 179-181" C.

Example 5.-Ethyl (3 carbo'benzyloxy 8 chloro 4,

.10 dioxo 5 hyafoxy 1,2,3,4,4a,9,9a,10 octahydro- 2 anthryl)nitr0acetateTo a stirred solution of benzyl 8-chloro-5-hydroxy-l,4, 4a,9,9a,10hexahydro 4,10 dioxo anthracene-B-carboxylate (100 mg) in 7 ml. ofsodium dried toluene, under a nitrogen atmosphere, was added 50 mg. of a50% .3 sodium hyd-ride in oil suspension followed immediately by 0.14ml. of ethyl nitroacetate. The mixture was stirred at room temperaturefor two hours, by which time no significant quantity or startingmaterial could be detected .oil was purified by chromatography on silicagel (100- 200 mesh) using benzene: petroleum ether (9:1) as eluent.

The nitroacetate adduct was characterized by its infrared andultraviolet spectra.

Example 6.'-3 carbobenzyloxy 8 chloro 2 nitromethyl 4,10 dioxo 5 hydroxy1,2,3,4,4a,9,9a,10 octahydroanthracene To a stirred solution of "benzyl8-chloro-5-hydroXy-1, 4,4a,9,9a,l-heXahydro-4,lO-dioxo-anthracene 3carboxylate (300 mg.) is 10 ml. of sodium dried toluene, under anitrogen atmosphere, was added 105 mg. of a 50% sodium hydride in oilsuspension followed immediately by 0.3 ml. of nitromethane. The mixturewas stirred at room temperature for 1.5 hours. The reaction mixture wasacidified by the cautious addition of glacial acetic acid. Afterdilution with ethyl acetate the solution was washed with 20 ml. of 1 Nhydrochloric acid and twice with water. The dried solution wasconcentrated to a gum in vac. which was triturated with ml. of ether.The yield of crystalline 3-carbobenzyloxy-8-chloro-2-ni- ,tromethyl 4,10dioxo 5 hydroxy 1,2,3,4, 4a,9,9a,

lfl-octahydroanthracene was 160 mg; M.P. 163-165 C.

Example 7.3 carboxy 8 chloro 2 nitromethyl 4,

dioxo 5 hydroxy 1,2,3,4,4a,9,9a,10 octahydroanthracene 3 carbobenzyloxy8 chloro 2 nitromethyl 4,10- dioxo 5 hydroxy 1,2,3,4,'4a,9,9a,10octahydroanthracene (150 mg.) was dissolved in 50 ml. of methylCellosolve with the aid of heat. The solution was cooled in an ice bath,flushed with nitrogen, and 30 mg. of 10% was removed by evaporationunder vacuum, the temperature of the solution being maintained at orbelow room temperature. The residual pale yellow solid was slurried inether, collected in a filter and dried in vac. at room temperature. Theyield of 3-canboxy-8-chloro- 2 nitromethyl 4,10 dioxo 5 hydroxy 1,2,3,4,4a, 9,9a,=10 octahydronathracene acid was mg; M.P. 142 C. with theevolution of gas. 2

What is claimed is:

1. A compound selected from the group consisting of those of theformula:

hno

wherein X is selected from the group consisting of hydrogen, chlorineand bromine, R is selected from the group consisting of hydrogen,carboxy, lower carbalkoxy and phenyl lower carbalkoxy, and Z is selectedfrom the group consisting of hydrogen, lower carbalkoxy and loweralkanoyl, and tautomers thereof.

2. 3 carbooenzyloxy 8 chloro 2 (1 nitroacetonyl) 4,10 dioxo 5 hydroxy1,2,3,4,4a,9,-9a, l0 octahydroan-thracene.

3. '3 carboxy 8 chloro 2-(1 nitroacetonyl) 4,10- dioxo 5 hydroxy1,2,3,4,4a,9,9a,10 -octahydroanthracene.

4. Ethyl (3 carbobeuzyloxy 8 chloro 4,10 dioxo- 5 hydroxy1,2,3,4,4a,9,9a,10 octahydro 2 anthryl)- nitroacetate.

5. 3 carbobenzyloxy 8 chloro 2 nitromethyl-4,10- dioXo 5 hydroxy1,2,3,4,4a,9,9a,-l0-octahyd1=oanthracene.

6. 3 carboxy 8 chloro 2 nitromethyl 4,10- dioxo 5 hydroxy1,Q,3,4,4a,9,9-a,1O octahydroanthracene.

References Cited by the Examiner UNITED STATES PATENTS 3,002,993 10/61Wilkinson et al 260558 LEON ZITVER, Primary Examiner.

DANIEL D. HORWITZ, Examiner.

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF THOSE OF THEFORMULA: